3-alkyl-3-amino-6-hydroxy-3, 4-dihydro-coumarins



United States Patent Ofiice 3,161,655 Patented Dec. 15, 1964 Thisapplication is a division of application Serial No. 35,132, filed June10, 1960, now abandoned.

This invention relates to derivatives of phenylalanine and to processesfor preparing the same.

The novel compounds of the present invention having anti-hypertensiveactivity have the general formula:

where R is selected from the group consisting of hydrogen and loweralkanoyl radicals and R is a straight chain lower alkyl radicalcontaining from one to about four carbon atoms. Also included in thepresent invention are the non-toxic acid addition salts of the abovecompounds wherein R is hydrogen. Preferred acid addition salts are thoseof non-toxic mineral acids such as hydrochloric acid, hydrobromic acidand sulfuric acid.

The compound 3-methyl-3-amino-6-hydroxy-3,4-dihydrocoumarin has greateractivity in the treatment of hypertension than the previously knowna-methyl-fi-GA- dihydroxyphenyl) alanine disclosed in United StatesPatent 2,868,818, and accordingly is used in smaller dosage. Othercompounds of the present invention are likewise highly active.

The compounds of the present invention are eifective in the treatment ofhypertension when administered orally in a daily dosage of about 0.15 toabout 6 grams per day, preferably subdivided throughout the day. Thepreferred dosage range is from about 0.3 to about 3 grams per day. Thesecompounds may be administered in gelatin capsules containing about 0.1to about 0.5 gram of active ingredients or in tablets containing fromabout 0.1 to about 0.5 gram of active ingredients plus conventionalexcipients such as corn starch, lactose, magnesium stearate as alubricating agent, flavoring agents and the like. These compounds mayalso be administered orally as an aqueous suspension. Alternatively thecompounds of the present invention may be administered parenterally insterile solution in suitable solvents, such as water, in

the daily amounts of about 0.1 to about 2 grams per day,,

preferably subdivided throughout the day.

A further advantage of the compounds of this invention is the lowincidence of side effects. One sideeffect which has been observed inpreviously known hypertensive agents is the tendncy to cause drowsiness.This is attributable to lowering of the norepinephrine level in thebrain. The compound a-methyl-,8-(2,3-dihydroxyphenyDaIanine causes onlya very slight diminution in the brain norepinephrine level, andtherefore causes virtually no drowsines.

The preparation of compounds of the present invention may be illustratedby the preparation of 3-amino-3- methyl-8-hydr0Xy-3,4-dihydroeoumarinfrom 2,3-dirnethoxybenzaldehyde according to the flow sheet given below.

N Hg VII The compound 2,3-dimethoxybenzaldehyde (I) is reacted withnitroethane in the presence of a base such as or benzene under reflux orother elevated temperature conditions, thereby producing1-(2-nitropropenyl)-2,3- dimethoxybenzene (II). This compounds isreacted with a reducing agent, preferably iron in an acidic medium suchas aqueous hydrochloric acid, which results in the formation of 1 (2,3dimethoxyphenyl) 2 propanone (III).

Reaction of 1 (2,3-dimethoxyphenyl)-2-propanone (III) with ammoniumcarbonate and a water-soluble cyanide salt such as potassium cyanide,sodium cyanide, or ammonium cyanide in an aqueous medium results in theformation of S-methyl-S-(2,3-dimethoxybenzyl) hydantoin (IV). Thisreaction may be carried out either at room temperature or at an elevatedtemperature. The reaction requires about 3 to 4 days at room temperatureand about 12 to 24 hours at temperatures in the range of 5060 C.

The S-methyl-S-(2,3-dimethoxybenzyl)hydantoin can be converted to3-amino-3-methyl-8-hydroxy-3,4-dihydrocoumarin (VII) by a sequence ofreactions in which a-methyl-B-(2,3-dimethoxyphenyl)alanine and a mixtureof acid addition salts consisting primarily of 3-amino-3- methyl 8hydroxy-3,4-dihydrocoumarin hydrobromide (VI) and a minor amount ofu-methyl-fi-(2,3-dihydroxyphenyl)alanine hydrobromide are formed asintermediates.

Reaction of S-methyl-S-(2,3-dimethoxybenzyl)-hydantoin (IV) with a basesuch as barium hydroxide, calcium hydroxide, or sodium hydroxide in anaqueous medium at elevated temperature, as for example at atmosphericpressure and reflux temperature (about 100 C.) or in a bomb underpressure at about 150 C., results in conversion of the hydantoin toa-methyl-B-(2,3-dimethoxyphenyl)alanine (V). Where barium hydroxide orcalcium hydroxide is used as a base, the alkaline earth metal ion insolution can be precipitated as the sulfate or carbonate, and thereafterthe product can be recovered from the aqueous solution by evaporation.Other methods of separating of the product from solution will be obviousto those skilled in the art.

Hydrolysis of a-methyl-B-(2,3-dimethoxyphenyl)-alanine (V) can beaccomplished with a concentrated aqueous solution of a strong mineralacid such as hydrobromic acid or hydrochloric acid at elevatedtemperature of about 90 C. or higher. A preferred acid is hydrobromicacid having a concentration of about 35 percent to about 55 percent.Excellent results are obtained using 48 percent aqueous hydrobromic acidat the reflux temperature of 126 C. The hydrolysis product under theseconditions is a mixture in which the principal product is 3-amino-3-methyl 8 hydroxy-3,4-dihydrocoumarin hydrobromide (VI). This compound isthe delta-lactone of a-methyl- B-(2,3-dihydroxyphenyl)alaninehydrobromide, which is formed in minor amounts. This reaction mixturecan be separated into its components by contact with acetone, in whicha-methyl-B-(2,3-dihydroxyphenyl)alanine hydrobromide is soluble and3-amino-3-methyl-8-hydroxy- 3,4-dihydrocoumarin hydrobromide isinsoluble.

The mixture of a-methyl-fi-(2,3-dihydroxyphenyl)- alanine hydrobromideand 3-amino-3-methyl-8-hydroxy- 3,4-dil1ydrocoumarin hydrobromide (VI)can be converted to substantially pureoz-methyl-fi-(2,3-dihydroxyphenyl)alanine by reaction with waterfollowed by reaction with an aqueous solution of a base such as ammoniaor sodium bicarbonate, or a weakly basic anion exchange resin for asubstantial length of time suflicient for hydrolysis of the3-amino-3-methyl-8-hydroxy 3,4-dihydrocoumarin hydrobromide (forexample, one hour or longer). Where the desired product is3-arnino-3-methyl- 8-hydroxy-3,4-dihydrocoumarin (VII), the hydrobromide(VI) is neutralized to pH 6 to 8 with a weak base such as sodiumbicarbonate or ammonium hydroxide, and the precipitate is immediatelyfiltered. Alternatively, the neutralization can be carried out in anon-aqueous organic solvent, such as methylene chloride or ethanol.

VIII

l(CHaCO)O CH3 NBC 0 CH3 0 C 0 OH:

I CHg-CCOOH NHCOCH:

CHsCOO- These compounds can be separated by fractional crystallizationfrom a solvent such as isopropanol, ethanol, or the like. Acylation canalso be accomplished using other anhydrides of lower aliphaticcarboxylic acids, e.g., propionic anhydride and butyric anhydride.

The methods for preparing 3-methyl-3-amino-8-hydroxy-3,4dihydrocoumarinand derivatives thereof described above can also be used for preparinghomologs such as 3-ethyl-3-amino-8-hydroxy-3,4-dihydrocoumarin, 3 propyl3 amino 8 hydroxy 3,4 dihydrocoumarin, 3 butyl 3 amino 8 hydroxy 3,4dihydrocoumarin and their derivatives. These compounds can be preparedby reacting an aldehyde having the general formula:

where R, is a lower alkyl radical, with a nitroalkane having the generalformula:

such as l-uitropropane or l-nitrobutane under the conditrons indicatedfor the reaction of 2,3-dimethoxybenzaldehyde. The product thus obtainedhas the general formula:

This compound is reacted with iron and hydrochloric acid as previouslydescribed to form a ketone having the general formula:

1 form a hydantoin having the general formula:

. This compound is hydrolyzed with a concentrated solution of a strongmineral acid, prefer-ably 48 percent hydrobromic acid and alternativelyanother acid such as concentrated hydrochloric acid, to produce amixture of acid addition salts having the formulas:

Where X is. as heretofore defined. Rapid neutralization of a lactoneacid addition salt with an aqueous base such as ammonia yieldspredominantly a lactone having th formula:

and

as well as the non-toxic acid addition salts thereof, are active asanti-hypertensive agents.

Acylated derivatives having the formula:

where R is a lower alkanoyl radical, can be prepared by reaction of anar-(lower alkyl)-5-(2,3-dihydroxyphenyl)- alanine or an acid additionsalt thereof, with an acid anhydride such as acetic anhydride orpropionic anhydride in the presence of a base such as sodium hydroxideor pyridine. These compounds have anti-hypertensive activity.

6. This invention will now be described in detail with reference to theexamples which follow.

EXAMPLE 1 1-(2-Nitr0-1-Pr0penyl) -2,3-Dimeth0xybenzene A mixture of 166g. (1.0 mole) of 2,3-dimethoxybenzaldehyde, 82.5 g. 1.1 mole) ofnitroethane, 200 ml. of toluene, and 20 ml. of n-butylamine is heated atthe reflux temperature. The distillate is passed through a separatorwhereby the lower water layer is removed and only the organic layer isreturned to the reaction vessel. After approximately eighteen hours, theexpected amount of water has separated. The solution is concentrated toa volume of approximately 200 ml. under reduced pressure. The solutionis chilled to about 0 C., and the resulting crystals of1-(2-nitropropenyl)-2,3-dimethoxybenzene are collected by filtration.Yield 154 g.; M.P. 79-81 C.

In a similar manner to the above, but using 98 g. of l-nitropropane, 113g. of l-nitrobutane or 129 g. of 1- nitropentane in place ofl-nitropropane there is obtained respectively1-(2-nitro-l-pentenyl)-2,3-dimethoxybenzene ofl-(2-nitro-1-hexenyl)-2,3-dimethoxybenzene.

EXAMPLE 2 J-(Z-Nitropropenyl) -2,3-Dieth0xybenzene A mixture of 194 g.(1.0 mole) of 2,3-diethoxybenzaldehyde, 82.5 g. 1.1 mole) ofnitroethane, 200 ml. of toluene, and 20 ml. of n-butvlamine is heated atthe reflux temperature. The distillate is passed through a se aratorwhereby the lower water layer is removed and only the organic layer isreturned to the reaction vessel. The reaction is continued untilapproximately 18 ml. (1 mole) of water has formed. The solution is thenconcentrated under reduced pressure to remove toluene and butylamine,leaving a residue of substantially pure 1-(2- nitropropenyl) -2, 3-d.iethoxybenzene.

In a similar manner to the above, but using 98 g. of l-nitropropane, 113g. of l-nitrobutane or g. of 1- nitropentane one obtains respectively,1-(2-nitro-l-butenyl)-2,3-diethoxybenzene, 1-(2 nitro-l-pentenyl)-2,3-diethoxybenzene, or 1-(2-nitro-1-hexenyl)-2,3-diethoxybenzene.

EXAMPLE 3 I-(2,3-Dimeth0xyphenyl)-2-Pr0pan0ne In a 2-liter creased(Morton) flask are combined 150 g. (0.67 mole) of1-(2-nitropropenyl)-2,3-dimethoxybenzene, prepared as in Example 1, 260g. of iron powder (40 mesh), 2.6 g. of ferric chloride hexahydrate and515 ml. of water. With good stirring the mixture is heated to the refluxtemperature. During the course of the next two hours, there is added 260m1. of 38% aqueous hydrochloric acid, while the mixture is stirred andheated under reflux. The mixture is stirred and heated for 4.5 hoursfurther under reflux. The mixture is cooled to about 20 C., and filteredthrough a pad of diatomaceous earth. The aqueous filtrate is acidifiedwith 2.5 N hydrochloric acid to a pH of approximately 2. The filter cakeis washed successively with four -ml. portions of benzene, and eachportion is used to extract the aqueous filtrate. The combined organiclayers are washed to neutrality with four ml. portions of water. Theorganic layer is then stirred well with 330 ml. of 10% aqueous sodiumbisulfite for an hour. The organic phase is separated and washed withseven 150 ml. portions of water. The organic phase is then concentratedto remove benzene, leaving a residue of 122.2 g. of substantially purel-(2,3-dimethoxyphenyl)- 2-propanone.

By use of the above procedure, but with replacement of the'1-(2-nitropropenyl)-2,3-dimethoxybenzene by 0.67 gram mole of1-(2-nitro-1-butenyl)-2,3-dimethoxybenzene,1-(2-nitro-l-phentenyl)-2,3-dimethoxybenzene, 1-(2-nitro-l-hexenyl)-2,3-dimethoxybenzene, all prepared as 7 in Example 1,or by 2,3-diethoxy-l-(2-nitropropenyl) benzene,1,2-diethoxy-3-(2-nitrobutenyl)benzene,1,2-diethoxy-3-(2-nitropentyl)benzene, or 1,2-diethoxy-3-(2-nitrohexenyl)benzene, all prepared as in Example 2, there is obtainedrespectively, 1-(2,3-dirnethoxyphenyl)-2- butanone,1-(2,3-dimethoxyphenyl)-2-pentanone, 1-(2,3- dimethoxyphenyl-2-hexanone, 1- (2,3 -diethoxyphenyl -2- propanone,1-(2,3-diethoxyphenyl)-2-butanone, 1-(2,3-diethoxyphenyl)-2-pentanone or1-(2,3-diethoxyphenyl)-2- hexanone.

EXAMPLE 4 5 -Melhyl-5 (2,3-Dimethoxyphenyl )Hydantoin A mixture of 37 g.(0.19 mole) of l-(2,3-dimethoxyphenyl)-2-propanone, prepared as inExample 3, 150 g. of ammonium carbonate, 32.6 g. of potassium cyanide,225 ml. of absolute ethanol and 225 ml. of water is stirred at roomtemperature for about 65 hours, then heated at 55-60 C. for two hours.The mixture is then concentrated to approximately half its volume underreduced pressure and the resulting suspension of crystals of5-methyl-5-(2,3-dimethoxyphenyl)hydantoin after cooling to roomtemperature is filtered. The product is washed with water and ether andwhen dry, weighs 46.2 g. (91%), M.P. l99-201 C.

By following the above procedure, but using in place of1-(2,3-dimethoxyphenyl)-2-propanone, 0.19 gram-mole of1-(2,3-dimethoxyphenyl)-2-butanone, l-(2,3-dimethoxyphenyl)-2-pentanone,l-(2,3-dimethoxyphenyl)-2-hexanone, l-(2,3-diethoxyphenyl)-2-propanone,

l- (2,3-diethoxyphenyl -2-butanone,

1- 2,3-diethoxyphenyl -2-pentanone or 1-(2,3-diethoxyphenyl)-2-hexanone,

one obtains respectively, S-ethyl-S-(2,3-dimethoxyphenyl)hydantoin,

5 -n-propyl-5 2,3-dimethoxyphenyl) hydantoin, 5-nbutyl-5-(2,3-dimethoxyphenyl)hydantoin,5-methyl-5-(2,3-diethoxyphenyl)hydantoin,5-ethyl-5-(2,3-diethoxyphenyl)hydantoin,5-n-propyl-5-(2,3-diethoxyphenyl)hydantoin, or S-n-butyl-S-(2,3-diethoxyphenyl) hydantoin.

EXAMPLE 5 a-Methyl-fl-(2,3-Dihydroxyphenyl)Alanine A mixture of 20 g.(0.0756 moles) of 5-methyl-5-(2,3- dimethoxyphenyl)hydantoin (IV) and200 ml. of 48% aqueous hydrobromic acid was refluxed under a nitrogenatmosphere for 44 hours. The hydrobromic acid was evaporated in vacuo.The residue was dissolved in 50 ml. of tert.-butanol, heated to 60 C.for about 20 minutes, and the tert.-butanol evaporated in vacuo. Theresidue was then stirred for about 20 minutes in 100 ml. of acetone andthe insoluble material removed by filtration. Thea-methyl-/8-(2,3-dihydroxyphenyl)alanine hydrobromide in solution wasconverted to the free amino acid by adding 4.9 ml. of ethylene oxide andallowing the mixture to stand at 5 C. for about 16 hours. The crudea-methylfl-(2,3-dihydroxyphenyl)alanine was filtered, washed with two10-ml. portions of acetone, and air dried. Yield 13.1 g. (82%). Thecrude product was slurried in 75 ml. of water. Sulfur dioxide was passedinto the solution until a clear solution was obtained. The clearsolution was decolorized with one gram of Darco G-60 charcoal at roomtemperature for minutes, the charcoal filtered, and the solutionconcentrated in vacuo to a volume of approximately 50 ml. The mixturewas allowed to stand for about 15 hours at 5 C., resulting in thecrystallization of u-methyl-p-(2,3-dihydroxyphenyl)alanine. The productwas filtered, washed with two IO-ml. portions of ice water, and dried at100 C. in vacuo. Yield 8.3 g. (52%); M.P. 248 C., resolidified onfurther heating, solid at 300 C. Concentration of the mother liquors toabout 10 ml. followed by cooling gave a second crop; yield 3.56 g. (22%Each crop was recrystallized by dissolving in about 10 ml. of watersaturated with sulfur dioxide per gram of solid, and treatingsuccessively with about 10% of Darco-G60 and about 5% of ethylenediamine tetraacetic acid tetrasodium salt (each based on the weight ofproduct) and concentrated in vacuo to about 5 ml. per gram. Each of theconcentrated solutions was allowed to stand at 5 C. for about 15 hours,causing precipitation of crystalline a-methyl-fi-(2,3-dihydroxyphenyl)alanine. Yield 7.82 g., sinter at 249 C. (solid at 300 C.); 2.2 g.,sinter at 250 C. (solid at 300 0.), respectively.

EXAMPLE 6 a-Methyl-B-(2,3-Dimeth0xyphenyl)Alanine A mixture of 26.4 g.(0.1 mole) of 5-methyl-5-(2,3- dimethoxyphenyl)hydantoin, prepared as inExample 4, g. of barium hydroxide octahydrate and 700 ml. of water isheated under reflux which eflicient stirring for 88.5 hours, thusforming the barium salt of a-methyl-p- (2,3-dimethoxyphenyl)alanine.Carbon dioxide is then bubbled through the mixture until theprecipitation of barium carbonate is essentially complete and thesuspension is filtered. To the filtrate is added carefully 2 N sulfuricacid until no more barium sulfate precipitates. The final pH isapproximately 7. The barium sulfate is removed by filtration and thefiltrate is concentrated to give a crystalline residue weighing 31.1 g.,M.P. 234-238 C. Residual water is removed by adding successive 50 ml.portions of absolute ethanol and codistilling. The crystalline residue,weighing 25.7 g., is slurried in 250 ml. of boiling absolute ethanol,and after cooling to room temperature, the crystalline producta-methyl-B-(2,3-dimethoxyphenyl)alanine, is collected, washed with coldabsolute alcohol, and dried at 100 C. in vacuo; weight, 18.9 g. (79%);M.P. 238.5-240 C.

EXAMPLE 7 u-Ethyl-fi-(2,3-Dimethoxyphenyl)Alanine A mixture of 9.3 g.(0.033 mole) of 5-ethyl-5-(2,3- dimethoxybenzyl)hydantoin, 46.5 g. ofbarium hydroxide, and 232 ml. of water is heated in a bomb withagitation at C. for 14 hours. The bomb contents are cooled to roomtemperature and transferred to a flask. Carbon dioxide is bubbled intothe reaction mixture until no more barium carbonate precipitates. Themixture is filtered, and 2 N sulfuric acid is added to the filtrateuntil no more barium sulfate precipitates. The mixture is again filteredand the filtrate concentrated to dryness. The solid material, which hasa weight of about 8.3 g., is suspended in 25 ml. of absolute ethanol,and the suspension is cooled and filtered. The soliddl-a-ethyl-B-(2,3-dimethoxyphenyl)alanine is washed with cold ethanoland ether and dried.

By use of the above procedure, but with replacement of the5-ethyl-5-(2,3-dimethoxybenzyl)hydantoin by 0.033 mole of 5 -n-propyl-52,3-dimethoxybenzyl hydantoin, S-n-butyl-S- (2,3-dimethoxybenzyl)hydantoin, 5 -methyl-5 2,3-diethoxybenzyl hydantoin, 5-ethyl-5-2,3-diethoxybenzyl hydantoin, S-n-propyl-S- (2,3-diethoxybenzylhydantoin, or 5 -n-butyl-5- 2,3-diethoxybenzyl hydantoin, one obtainsrespectively a-ethyl-fi- (2,3-dimethoxyphenyl) alanine, u-n-propyl-B-2,3-dimethoxyphenyl) alanine, u-n-butyl-fi- (2,3-dimethoxyphenylalanine, u-methyl-fi- (2,3-diethoxyphenyl) alanine, a-ethyl-fi-2,3-diethoxyphenyl alanine, a-n-propyl-B- 2,3-diethoxyphenyl) alanine,or a-n-butyl-p- (2,3-diethoxyphenyl) alanine.

9 EXAMPLE 8 3-Amin0-3-Methyl-8 Hydroxy 3,4 Dihydrocourmarin HydrobromideA mixture of 30.0 g. of a-methyl-e-(2,3-dimethoxyphenyl)alanine and 300ml. of 48% hydrobromic acid was purged with nitrogen, and refluxed for2.5 hours, cooled, allowed to stand at room temperature for about 16hours under a nitrogen atmosphere, and concentrated to dryness in vacuo.The crystalline residue was dissolved in 100 ml. of tert.-butanol, whichwas evaporated in vacuo; this procedure was repeated twice. The finalresidue was slurried in 100 ml. of hot acetone to dissolve impurities,and the slurry was cooled and filtered, yielding3-amino-3-methyl-8-hydroxy-3,4-dihydrocoumarin hydrobromide. Yield 28.8g. (84%); equivalent Weight 276 (theoretical 274).

Analysis for Br: Calculated, 29.17%; found, 28.99%.

In a second run the reflux time was 22.5 hours and the product wasrecovered in the same manner as in Example 8 except that the extractionwith acetone was omitted. A crystalline product consisting essentiallyof 3-amino-3-methyl-8-hydroxy-3,4 dihydrocoumarin was obtained.

Reaction of a-methyl-fl-(3,4-diethoxyphenyl) alanine according to theprocedure of Example 7 results in the formaion of3-amino-3-methyl-8-hydroxy 3,4 dihydrocoumarin.

Reaction of ot-ethyl-fi-(3,4-dimethoxyphenyl) alanine orot-propyl-fi-(3,4-dimethoxyphenyl)alanine according to the procedure ofExample 7 results in the formation of 3- amino-3-ethyl-8 hydroxy 3,4dihydrocoumarin or 3- amino-3-propyl-8-hydroxy-3,4 dihydrocoumarin,respectively.

EXAMPLE 9 3-Amin0-3-Methyl-8-Hydroxy-3,4-Dihydrocouma'rin One gram of3-amino-3-methyl-8-hydroxy-3,4-dihydrocoumarin hydrobrornide wasdissolved in 15 ml. of water and the pH was adjusted to 7.6 With 6 Nammonium hydroxide, the precipitate was filtered, washed with water, anddried in vacuo. This precipitate was identified as 3-amino-3-methyl-8-hydroxy-3,4 dihydrocoumarin (VII). Yield 400 mg. (57%The product sintered at 225 C. and underwent incomplete decompositionfrom 225 to 300 C. max. 278 mm, B percent 132.

Analysis.-Calculated for C H O N: C, 62.16%; H, 5.74%. Found: C, 61.98%;H, 6.00%.

EXAMPLE 1O 3-AmiIw-S-Methyl-8-Hydr0xy-3,4-Dihydr0c0umarin To a solutionof 19.4 g. of sodium bicarbonate in 120 ml. of Water was added 19.4 g.(0.071 mole) of B-amino- 3-rnethy1-8-hydroxy-3 ,4 dihydrocoumarinhydrobromide in small amounts at a time, causing vigorous foaming of thereaction mixture. The reaction mixture was filtered, and the solidmaterial was washed with water and petroleum ether, and dried in vacuoat C. Yield 12.3 g. sinter at 220222 C. One gram of the crude productwas dissolved in ml. of acetonitrile and refluxed. The insolublematerial was filtered off, and the reaction mixture was cooled,filtered, and washed with acetonitrile and ether. Yield 740 g., M.P.229230 C. (partial melting).

Analysis-Calculated for C H NO C, 62.16%; H, 5.76%; N, 7.25%. Found: C,62.25%; H, 6.00%, N, 7.52%.

EXAMPLE l1 3 A cetamido-S-Methyl-S-A cetoxy-3,4-Dihydr0c0umarin and N -Acetyl-ot-Mezhtyl-fl-(2,3-Diacet0xyphenyl A lam'ne A mixture of 1.5 g. ofot-methyl-B-(2,3-dihydroxyphenyl)alanine, 10 ml. of acetic anhydride,and 8 ml. of pyridine was heated at 90 C. for two hours, effectingcomplete solution. This solution was concentrated to drynose. Theresidue was dissolved in 5 ml. of water and the solution was acidifiedto a pH of about 2 with 2.5 N hydrochloric acid. The resultingprecipitate was filtered, washed with water and dried. Yield 1.33 g.Recrystallization from hot isopropanol yielded pure3-acetamido-3-methyl- 8-acetoxy-3,4-dihydrocoumarin; M.P. 187.5 C. Theinfrared spectrum and nuclear magnetic resonance data are consistentwith structure.

Analysis.Calculated for C H O N: C, 60.64%; H, 5.45%; N, 5.05%. Found:C, 60.55%; H, 5.53%; N, 4.85%.

Concentration of the mother liquors gave a second compound, M.P.207.5-209 C., 7\ max. (Nujol) 5.66 5.8,u, 6.4211,. This compound wasidentified as N-acetyla-methyl-fi- (2,3-diacetoxyphenyl) alanine.

We claim:

1. A compound selected from the group consisting of (1) a compound ofthe formula:

lRa cfiz \NHRI Where R is selected from the groups consisting ofhydrogen and lower alkanoyl, and R is straight chain lower alkyl, and(2) anon-toxic acid addition salt thereof.

2. 3-methyl-3-amino-8-hydroxy-3,4-dihydrocoumarin.

References Cited in the file of this patent UNITED STATES PATENTS"3,049,550 Spencer et al. Aug. 14, 1962

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (1) A COMPOUND OFTHE FORMULA